Abstract Adverse effects of excessive drinking are widespread in terms of the increased health care, loss of productivity, crime, accidents, and myriad emotional and personal costs. Understanding the factors that contribute to the development and persistence of excessive alcohol consumption is crucial for improved prevention, education and intervention strategies. The goal of our study is to evaluate the role of subjective and physiologic responses to alcohol in the escalation and maintenance of excessive drinking in adults. Our paradigm integrates human laboratory alcohol challenge with longitudinal assessment of drinking and related behaviors to discern whether alcohol responses predict future drinking problems in young heavy drinkers versus light drinker controls. In the last award phase, we also provided an initial laboratory re-examination of alcohol responses 5 years after initial testing to determine the stability or change in alcohol responses over time and how they relate to drinking behaviors. Thus far, findings from our carefully designed laboratory and intermediate-term follow-up investigation has advanced new discoveries and challenged existing paradigms. Compared with light drinkers, heavy social drinkers have greater sensitivity to alcohol's stimulating and rewarding (liking, wanting) effects and lower sensitivity to sedative effects. These effects predicted future binge drinking through six years of follow-up. As the sample is now aging to their thirties, a developmental period when binge drinking is less normative, we now propose several extensions of the longitudinal aspects of the study. In Aim 1, we will extend follow-up during early middle adulthood in our existing cohorts (n=290) to discern binge drinking severity, alcohol use disorder symptoms, and drinking consequences during this transitional phase and evaluate the role of early-adult stimulating, rewarding, and sedating alcohol responses in predicting these behaviors. In Aim 2, we will conduct a second re-examination testing of alcohol response one decade after initial testing. This will enable full direct and longitudinal tests of incentive-sensitization, reward sensitivity and low response models of the development of addictive behavior. In Aim 3, we propose to conduct alcohol challenge testing in a new cohort of persons with alcohol dependence who are not seeking treatment (n=104) and compare them to existing heavy and light drinker cohorts (n=290). The information from this translational laboratory and longitudinal investigation will provide an evidence-based test of the role of alcohol response to escalations and maintenance of excessive drinking. Results have already advanced our knowledge of how alcohol responses predict future course of drinking, and the proposed extensions and new directions will further elucidate new empirical insights into the propensity for excessive and harmful drinking.